The present invention relates to a novel process for the preparation of 5-cyanophthalide which is an intermediate used for the manufacture of the well known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran-carbonitrile.
Citalopram is a well known antidepressant drug that has now been on the market for some years and has the following structure: 
It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486.
Citalopram may be prepared by the process described in U.S. Pat. No. 4,650,884, according to which 5-cyanophthalide is subjected to two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively, and the resulting compound of the formula 
is subjected to a ring closure reaction by dehydration with strong acid.
Enantiomers of citalopram may be prepared by the method described in U.S. Pat. No. 4,943,590, i.e. by separating the enantiomers of the intermediate of Formula II and performing enantioselective ring closure in order to obtain the desired enantiomer.
Thus, 5-cyanophthalide is an important intermediate for the manufacture of citalopram and it is important to produce this material in an adequate quality, by a convenient process and in a cost-effective way.
A method for the preparation of 5-cyanophthalide has previously been described in Bull. Soc. Sci. Bretagne, 1951, 26, 35 and in Levy and Stephen, J. Chem. Soc., 1931, 867. By this method, 5-aminophthalide is converted to the corresponding 5-cyanophthalide by diazotation followed by reaction with CuCN. 5-Aminophthalide was obtained from 4-aminophthalimide by a two step reduction procedure.
Synthesis of certain alkyl- and phenylnitriles from acid chlorides is described in Tetrahedron Letters, 1982, 23, 14, 1505-1508, and in Tetrahedron, 1998, 54, 9281.
Though a number of other methods failed, it has now been found that 5-cyanophthalide may be prepared in high yields by a convenient, cost-effective one-pot procedure from 5-carboxyphthalide.
Accordingly, the present invention provides a novel method for the preparation of 5-cyanophthalide 
comprising reaction of 5-carboxyphthalide 
with a dehydrating agent and a sulfonamide of the formula H2N-SO2-R (Formula V) wherein R is
a) NH2, C1-6 alkyloxy, phenyloxy,
b) phenyloxy substituted with halogen, C1-4-alkyl, cyano, hydroxy, C1-4-alkoxy, trifluoromethyl, nitro, amino, C1-4-alkylamino or di-C1-4-alkylamino, or
c) phenyl substituted with one or more electron withdrawing substituents in order to obtain 5-cyanophthalide.
Any suitable dehydrating agent may be used and the optimal agent may easily be determined by a person skilled in the art. Examples of suitable dehydrating agents are SOCl2, POCl3, PCl5, SOBr2, POBr3, PBr5, SOI2, POI3, PI5 and oxalylchloride. Preferably a chloro-containing agent, most preferably SOCl2, is used.
The term electron withdrawing substituent is intended to mean any substituent that is sufficiently electron withdrawing to allow the reaction to proceed, such as nitro, cyano, halogen, trifluoromethyl or aminosulfonyl. 3,5-Dinitrophenyl is an example of such a phenyl group substituted with electron withdrawing substituents.
In the method of the invention, the 5-carboxyphthalide reacts with the dehydration agent in order to form the corresponding 5-haloformyl derivative which then reacts with the sulfonamide of the formula V thereby forming the 5-cyanophthalide. During the latter reaction, a catalytic amount of an acid may be necessary. The 5-haloformyl derivative may, if desired, be isolated prior to further reaction. However, preferably the reaction is carried out as a one-pot procedure without isolation of the 5-haloformyl intermediate. Preferably the reaction proceeds via the 5-chloroformylphthalide.
The sulfonamide of Formula V used in the process is preferably sulfamide, i.e. a compound of Formula V wherein R is NH2.
The reaction is carried out neat or in a suitable solvent, such as sulfolane or acetonitrile. Preferably, sulfolane is used as the solvent.
Thus, in a preferred embodiment of the invention, 5-carboxyphthalide is reacted with sulfamide in the presence of SOCl2 in a sulfolane solution
The reaction is carried out at elevated temperature. When sulfolane is used as the solvent, the reaction is preferably carried out at about 120-150xc2x0 C.
5-Cyanophthalide may be isolated in a conventional way, e.g. by addition of water, filtration and subsequent washing of the crystals. Further purification may if desired be performed by recrystallisation.
Conveniently, 1.0 to 2.0 equivalents of sulfamide and dehydrating agent, respectively, are reacted with 1.0 equivalent 5-carboxyphthalide. Preferably, 1.0-1.2 equivalent sulfamide is used.
By the process of the invention, 5-cyanophthalide is obtained in high yields ( greater than about 70%). The process is much more convenient than the known process and uses more convenient and cheaper reactants and conditions. Furthermore, due to the fact that the process is a one-pot procedure the capacity is substantially increased and accordingly the costs are substantially reduced.
The 5-carboxyphthalide used as a starting material may be obtained by the methods described in U.S. Pat. No. 3,607,884 or German patent No. 2630927, i.e. by reacting a concentrated solution of terephthalic acid with formaldehyde in liquid SO3 or by electrochemical hydrogenation of trimellithic acid.